Erin M Parry, Camilla K Lemvigh, Stephanie Deng, Nathan Dangle, Neil Ruthen, Binyamin A Knisbacher, Julien Broséus, Sébastien Hergalant, Romain Guièze, Shuqiang Li, Wandi Zhang, Connor Johnson, Jaclyn Long, Shanye Yin, Lillian Werner, Annabelle Anandappa, Noelia Purroy, Satyen Gohil, Giacomo Oliveira, Pavan Bachireddy, Sachet A Shukla, Teddy Huang, Joseph D Khoury, Beenu Thakral, Michael Dickinson, Constantine Tam, Kenneth J Livak, Gad Getz, Donna Neuberg, Pierre Feugier, Peter Kharchenko, William Wierda, Lars Rønn Olsen, Nitin Jain, Catherine J Wu
Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells...
September 19, 2023: Cancer Cell
Ning-Ning Liu, Cheng-Xiang Yi, Lu-Qi Wei, Jin-An Zhou, Tong Jiang, Cong-Cong Hu, Lu Wang, Yuan-Yuan Wang, Yun Zou, Yi-Kai Zhao, Le-Le Zhang, Ya-Ting Nie, Yi-Jing Zhu, Xin-Yao Yi, Ling-Bing Zeng, Jing-Quan Li, Xiao-Tian Huang, Hong-Bin Ji, Zisis Kozlakidis, Lin Zhong, Christopher Heeschen, Xiao-Qi Zheng, Changbin Chen, Peng Zhang, Hui Wang
Although polymorphic microbiomes have emerged as hallmarks of cancer, far less is known about the role of the intratumor mycobiome as living microorganisms in cancer progression. Here, using fungi-enriched DNA extraction and deep shotgun metagenomic sequencing, we have identified enriched tumor-resident Aspergillus sydowii in patients with lung adenocarcinoma (LUAD). By three different syngeneic lung cancer mice models, we find that A. sydowii promotes lung tumor progression via IL-1β-mediated expansion and activation of MDSCs, resulting in suppressed activity of cytotoxic T lymphocyte cells and accumulation of PD-1+ CD8+ T cells...
September 19, 2023: Cancer Cell
Xubin Li, Jared Henderson, Max J Gordon, Irtiza Sheikh, Loretta J Nastoupil, Jason Westin, Christopher Flowers, Sairah Ahmed, Linghua Wang, Sattva S Neelapu, Paolo Strati, Qing Deng, Michael R Green
Li et al. present a resource of single-cell RNA sequencing (scRNA-seq) data from the infusion products of relapsed or refractory large B cell lymphoma (rrLBCL) patients treated with standard-of-care axicabtagene ciloleucel and identify features that are significantly different between products from responders and non-responders at 3-month followup by PET/CT, an important landmark for long-term outcomes.
September 15, 2023: Cancer Cell
Valentina Ferrari, Antonino Lo Cascio, Alessia Melacarne, Nina Tanasković, Alessandro M Mozzarelli, Luca Tiraboschi, Michela Lizier, Marta Salvi, Daniele Braga, Francesca Algieri, Giuseppe Penna, Maria Rescigno
Recent data have shown that gut microbiota has a major impact on the clinical response to immune checkpoint inhibitors (ICIs) in the context of solid tumors. ICI-based therapy acts by unlocking cognate cytotoxic T lymphocyte (CTL) effector responses, and increased sensitivity to ICIs is due to an enhancement of patients' tumor antigen (TA)-specific CTL responses. Cancer clearance by TA-specific CTL requires expression of relevant TAs on cancer cells' HLA class I molecules, and reduced HLA class I expression is a common mechanism used by cancer cells to evade the immune system...
September 13, 2023: Cancer Cell
Qi Cai, Sarah Warren, Violena Pietrobon, Markus Maeurer, Lei S Qi, Timothy K Lu, Marc J Lajoie, David Barrett, David F Stroncek, Francesco M Marincola
Successful implementation of adoptive cell therapy (ACT) of cancer requires comprehensively addressing biological and practical challenges. This approach has been largely overlooked, resulting in a gap between the potential of ACT and its actual effectiveness. We summarize the most promising technical strategies in creating an "ideal" ACT product, focusing on chimeric antigen receptor (CAR)-engineered cells. Since many requirements for effective ACT are common to most cancers, what we outline here might have a broader impact...
September 13, 2023: Cancer Cell
Kezhong Chen, Fan Yang, Haifeng Shen, Chenyang Wang, Xi Li, Olga Chervova, Shuailai Wu, Fujun Qiu, Di Peng, Xin Zhu, Shannon Chuai, Stephan Beck, Nnennaya Kanu, David Carbone, Zhihong Zhang, Jun Wang
We report a personalized tumor-informed technology, Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50 patient-specific variants to detect molecular residual disease (MRD) with a limit of detection of 0.004%. PROPHET and state-of-the-art fixed-panel assays were applied to 760 plasma samples from 181 prospectively enrolled early stage non-small cell lung cancer patients. PROPHET shows higher sensitivity of 45% at baseline with circulating tumor DNA (ctDNA)...
September 1, 2023: Cancer Cell
Beiping Miao, Zhaoqing Hu, Riccardo Mezzadra, Lotte Hoeijmakers, Astrid Fauster, Shangce Du, Zhi Yang, Melanie Sator-Schmitt, Helena Engel, Xueshen Li, Caroline Broderick, Guangzhi Jin, Raquel Gomez-Eerland, Lisette Rozeman, Xin Lei, Hitoshi Matsuo, Chen Yang, Ingrid Hofland, Dennis Peters, Annegien Broeks, Elke Laport, Annika Fitz, Xiyue Zhao, Mohamed A A Mahmoud, Xiujian Ma, Sandrine Sander, Hai-Kun Liu, Guoliang Cui, Yu Gan, Wei Wu, Yanling Xiao, Albert J R Heck, Wenxian Guan, Scott W Lowe, Hugo M Horlings, Cun Wang, Thijn R Brummelkamp, Christian U Blank, Ton N M Schumacher, Chong Sun
The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression...
August 31, 2023: Cancer Cell
Alberto Sanchez-Aguilera, Mariam Masmudi-Martín, Andrea Navas-Olive, Patricia Baena, Carolina Hernández-Oliver, Neibla Priego, Lluís Cordón-Barris, Laura Alvaro-Espinosa, Santiago García, Sonia Martínez, Miguel Lafarga, Michael Z Lin, Fátima Al-Shahrour, Liset Menendez de la Prida, Manuel Valiente
A high percentage of patients with brain metastases frequently develop neurocognitive symptoms; however, understanding how brain metastasis co-opts the function of neuronal circuits beyond a tumor mass effect remains unknown. We report a comprehensive multidimensional modeling of brain functional analyses in the context of brain metastasis. By testing different preclinical models of brain metastasis from various primary sources and oncogenic profiles, we dissociated the heterogeneous impact on local field potential oscillatory activity from cortical and hippocampal areas that we detected from the homogeneous inter-model tumor size or glial response...
August 28, 2023: Cancer Cell
Hirohito Yamaguchi, Mien-Chie Hung
The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers pubished in Cancer Cell, Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58.
August 26, 2023: Cancer Cell
Sophia J Wagner, Daniel Reisenbüchler, Nicholas P West, Jan Moritz Niehues, Jiefu Zhu, Sebastian Foersch, Gregory Patrick Veldhuizen, Philip Quirke, Heike I Grabsch, Piet A van den Brandt, Gordon G A Hutchins, Susan D Richman, Tanwei Yuan, Rupert Langer, Josien C A Jenniskens, Kelly Offermans, Wolfram Mueller, Richard Gray, Stephen B Gruber, Joel K Greenson, Gad Rennert, Joseph D Bonner, Daniel Schmolze, Jitendra Jonnagaddala, Nicholas J Hawkins, Robyn L Ward, Dion Morton, Matthew Seymour, Laura Magill, Marta Nowak, Jennifer Hay, Viktor H Koelzer, David N Church, Christian Matek, Carol Geppert, Chaolong Peng, Cheng Zhi, Xiaoming Ouyang, Jacqueline A James, Maurice B Loughrey, Manuel Salto-Tellez, Hermann Brenner, Michael Hoffmeister, Daniel Truhn, Julia A Schnabel, Melanie Boxberg, Tingying Peng, Jakob Nikolas Kather
Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks (CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation. Our transformer-based approach substantially improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms...
August 23, 2023: Cancer Cell
Pekka Ruusuvuori, Mira Valkonen, Leena Latonen
Artificial intelligence (AI) is rapidly gaining interest in medicine, including pathological assessments for personalized medicine. In this issue of Cancer Cell, Wagner et al. demonstrate superior accuracy of transformer-based deep learning in predicting biomarker status in CRC. The work has implications for increased efficiency and accuracy in clinical diagnostics guiding treatment decisions in precision oncology.
August 23, 2023: Cancer Cell
Krishnan K Mahadevan, Kathleen M McAndrews, Valerie S LeBleu, Sujuan Yang, Hengyu Lyu, Bingrui Li, Amari M Sockwell, Michelle L Kirtley, Sami J Morse, Barbara A Moreno Diaz, Michael P Kim, Ningping Feng, Anastasia M Lopez, Paola A Guerrero, Francesca Paradiso, Hikaru Sugimoto, Kent A Arian, Haoqiang Ying, Yasaman Barekatain, Lakshmi Kavitha Sthanam, Patience J Kelly, Anirban Maitra, Timothy P Heffernan, Raghu Kalluri
The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D , on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D -driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts...
August 23, 2023: Cancer Cell
Giulia Escobar, Katherine Tooley, Joan Pagès Oliveras, Linglin Huang, Hanning Cheng, Michelle L Bookstaver, Camilla Edwards, Eugene Froimchuk, Chang Xue, Davide Mangani, Rajesh K Krishnan, Natanael Hazel, Carola Rutigliani, Christopher M Jewell, Luca Biasco, Ana C Anderson
Stem-like CD8+ T cells are regulated by T cell factor 1 (TCF1) and are considered requisite for immune checkpoint blockade (ICB) response. However, recent findings indicate that reliance on TCF1+ CD8+ T cells for ICB efficacy may differ across tumor contexts. We find that TCF1 is essential for optimal priming of tumor antigen-specific CD8+ T cells and ICB response in poorly immunogenic tumors that accumulate TOX+ dysfunctional T cells, but is dispensable for T cell priming and therapy response in highly immunogenic tumors that efficiently expand transitory effectors...
August 17, 2023: Cancer Cell
Qian Huang, Liping Liu, Dakai Xiao, Zhi Huang, Wenjun Wang, Kui Zhai, Xiaoguang Fang, Jongmyung Kim, James Liu, Wenhua Liang, Jianxing He, Shideng Bao
Brain metastasis of lung cancer causes high mortality, but the exact mechanisms underlying the metastasis remain unclear. Here we report that vascular pericytes derived from CD44+ lung cancer stem cells (CSCs) in lung adenocarcinoma (ADC) potently cause brain metastases through the G-protein-coupled receptor 124 (GPR124)-enhanced trans-endothelial migration (TEM). CD44+ CSCs in perivascular niches generate the majority of vascular pericytes in lung ADC. CSC-derived pericyte-like cells (Cd-pericytes) exhibit remarkable TEM capacity to effectively intravasate into the vessel lumina, survive in the circulation, extravasate into the brain parenchyma, and then de-differentiate into tumorigenic CSCs to form metastases...
August 9, 2023: Cancer Cell
Kiarash Shamardani, Michelle Monje
Brain metastases cause cognitive impairment and impair quality of life. Sanchez-Aguilera et al. examine the effects of metastases on brain function leveraging in vivo electrocorticography and machine learning to reveal tumor model-specific changes in neural circuit dynamics and find that the electrophysiological profile predicts the presence and type of brain metastasis.
August 7, 2023: Cancer Cell
Yongchao Dou, Lizabeth Katsnelson, Marina A Gritsenko, Yingwei Hu, Boris Reva, Runyu Hong, Yi-Ting Wang, Iga Kolodziejczak, Rita Jui-Hsien Lu, Chia-Feng Tsai, Wen Bu, Wenke Liu, Xiaofang Guo, Eunkyung An, Rebecca C Arend, Jasmin Bavarva, Lijun Chen, Rosalie K Chu, Andrzej Czekański, Teresa Davoli, Elizabeth G Demicco, Deborah DeLair, Kelly Devereaux, Saravana M Dhanasekaran, Peter Dottino, Bailee Dover, Thomas L Fillmore, McKenzie Foxall, Catherine E Hermann, Tara Hiltke, Galen Hostetter, Marcin Jędryka, Scott D Jewell, Isabelle Johnson, Andrea G Kahn, Amy T Ku, Chandan Kumar-Sinha, Paweł Kurzawa, Alexander J Lazar, Rossana Lazcano, Jonathan T Lei, Yi Li, Yuxing Liao, Tung-Shing M Lih, Tai-Tu Lin, John A Martignetti, Ramya P Masand, Rafał Matkowski, Wilson McKerrow, Mehdi Mesri, Matthew E Monroe, Jamie Moon, Ronald J Moore, Michael D Nestor, Chelsea Newton, Tatiana Omelchenko, Gilbert S Omenn, Samuel H Payne, Vladislav A Petyuk, Ana I Robles, Henry Rodriguez, Kelly V Ruggles, Dmitry Rykunov, Sara R Savage, Athena A Schepmoes, Tujin Shi, Zhiao Shi, Jimin Tan, Mason Taylor, Mathangi Thiagarajan, Joshua M Wang, Karl K Weitz, Bo Wen, C M Williams, Yige Wu, Matthew A Wyczalkowski, Xinpei Yi, Xu Zhang, Rui Zhao, David Mutch, Arul M Chinnaiyan, Richard D Smith, Alexey I Nesvizhskii, Pei Wang, Maciej Wiznerowicz, Li Ding, D R Mani, Hui Zhang, Matthew L Anderson, Karin D Rodland, Bing Zhang, Tao Liu, David Fenyö
We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity...
August 2, 2023: Cancer Cell
Elizabeth P Henske, Liang Cheng, A Ari Hakimi, Toni K Choueiri, David A Braun
Chromophobe renal cell carcinoma (ChRCC) is the second most common variant histology RCC. ChRCC is distinct from clear cell RCC (ccRCC) in terms of genetics, genomics, metabolism, cell of origin, and response to targeted and immune therapies. The pathogenesis of ChRCC remains unclear, but current data suggest two potential mechanisms: mTORC1 hyperactivation through PTEN pathway mutations and mitochondrial dysfunction leading to oxidative stress. There are no specific approved treatments for ChRCC, although some responses to tyrosine kinase and mTOR inhibitors have been observed...
August 1, 2023: Cancer Cell
Davide Ceresa, Francesco Alessandrini, Sara Lucchini, Daniela Marubbi, Francesca Piaggio, Jorge Miguel Mena Vera, Isabella Ceccherini, Daniele Reverberi, Irene Appolloni, Paolo Malatesta
Glioblastoma progression in its early stages remains poorly understood. Here, we transfer PDGFB and genetic barcodes in mouse brain to initiate gliomagenesis and enable direct tracing of glioblastoma evolution from its earliest possible stage. Unexpectedly, we observe a high incidence of clonal extinction events and progressive divergence in clonal sizes, even after the acquisition of malignant phenotype. Computational modeling suggests these dynamics result from clonal-based cell-cell competition. Through bulk and single-cell transcriptome analyses, coupled with lineage tracing, we reveal that Myc transcriptional targets have the strongest correlation with clonal size imbalances...
July 20, 2023: Cancer Cell
Yi-Lu Zhou, Jie Hong
The role of gut microbiota and their sex-specific differences in colorectal cancer remain to be explored. In the current issue of Cancer Cell, Li et al. discovered that estrogen facilitates the colonization of Carnobacterium maltaromaticum in the mouse gut and exerts its anti-colorectal cancer effects by increasing the production of vitamin D3.
July 20, 2023: Cancer Cell
Xiaoling Li, Yunguan Wang, Su Deng, Guanghui Zhu, Choushi Wang, Nickolas A Johnson, Zeda Zhang, Carla Rodriguez Tirado, Yaru Xu, Lauren A Metang, Julisa Gonzalez, Atreyi Mukherji, Jianfeng Ye, Yuqiu Yang, Wei Peng, Yitao Tang, Mia Hofstad, Zhiqun Xie, Heewon Yoon, Liping Chen, Xihui Liu, Sujun Chen, Hong Zhu, Douglas Strand, Han Liang, Ganesh Raj, Housheng Hansen He, Joshua T Mendell, Bo Li, Tao Wang, Ping Mu
Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa)...
July 17, 2023: Cancer Cell
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